title: Adipocytes modulate the phenotype of human macrophages through secreted lipids.
abstract: Previous studies have shown accumulation and an enhanced proinflammatory profile of macrophages in adipose tissue of obese mice, indicating the presence of an interaction between adipocytes and macrophages in this tissue. However, the consequences of this interaction in humans are yet incompletely understood. In this study, we explored the modulating effects of adipocytes on the phenotype of macrophages in humans and studied the possible molecular pathways involved. Adipocyte-conditioned media (ACM) treatment of macrophages for 48 h strongly reduced the LPS-induced IL-12p40 secretion by macrophages, whereas the production of TNF-α and other cytokines remained largely unaffected. This effect was independent of the source of adipocytes. Interestingly, the level of inhibition correlated directly with body mass index (BMI) of the adipocyte donor. Because adipocytes release many different cytokines, adipokines, and lipids, we have separated the protein and lipid fractions of ACM, to obtain insight into the molecular nature of the soluble mediators underlying the observed effect. These experiments revealed that the inhibitory effect resided predominantly in the lipid fraction. Further studies revealed that PGE2 and linoleic and oleic acid were potent inhibitors of IL-12p40 secretion. Interestingly, concentrations of these ACM-derived lipids increased with increase in BMI of the adipocyte donor, suggesting that they could mediate the BMI-dependent effects of ACM. To our knowledge, these results provide first evidence that obesity-related changes in adipose tissue macrophage phenotype could be mediated by adipocyte-derived lipids in humans. Intriguingly, these changes appear to be different from those in murine obesity.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. I.R.Klein-Wieringa@lumc.nl
authors.forename: Inge R
authors.initials: IR
authors.lastname: Klein-Wieringa
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Andersen
authors.forename: Joanneke C
authors.initials: JC
authors.lastname: Kwekkeboom
authors.forename: Martin
authors.initials: M
authors.lastname: Giera
authors.forename: Badelog J E
authors.initials: BJ
authors.lastname: de Lange-Brokaar
authors.forename: Gerjo J V M
authors.initials: GJ
authors.lastname: van Osch
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zuurmond
authors.forename: Vedrana
authors.initials: V
authors.lastname: Stojanovic-Susulic
authors.forename: Rob G H H
authors.initials: RG
authors.lastname: Nelissen
authors.forename: Hanno
authors.initials: H
authors.lastname: Pijl
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Margreet
authors.initials: M
authors.lastname: Kloppenburg
authors.forename: René E' M
authors.initials: RE
authors.lastname: Toes
authors.forename: Andreea
authors.initials: A
authors.lastname: Ioan-Facsinay
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D015992:Body Mass Index; D002450:Cell Communication / Q000276:immunology; D017077:Culture Media, Conditioned; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism*; D019787:Linoleic Acid / Q000378:metabolism; D008055:Lipids; D008070:Lipopolysaccharides; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D019301:Oleic Acid / Q000378:metabolism; D010641:Phenotype; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D017077:Culture Media, Conditioned; D053762:Interleukin-12 Subunit p40; D008055:Lipids; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019301:Oleic Acid; D019787:Linoleic Acid; D015232:Dinoprostone